1. New frontiers in Diabetes management
Diabetes & macrovascular disease: Current views on the role of glucose control
Key-slides prepared and presented at CDMC on April 20, 2013 in Hanoi, Vietnam by
Mark Cooper, MD
Melbourne
Australia

2. Improvement in risk associated with a 1% reduction in HbA1c from 10 to 9%, and from 7 to 6%

3. Relative Risk Reduction
Each 1% reduction in HbA1c was associated with:
22% ↓ in risk of macrovascular event
26% ↓ in risk of microvascular event
22% ↓ in risk of death

4. UKPDS: Aggregate endpoints by treatments
Endpoint Intensive Conventional RR for Intensive Treatment
(N=2729) (N=1138)
Any diabetes
endpoint ( )
Diabetes-related
death ( )
All-cause
mortality ( )
MI ( )
Stroke ( )
Amputation/
PVD death ( )
Microvascular ( )
UKPDS Group, Lancet 1998

5. A factorial randomized trial of blood pressure lowering and intensive glucose control in 11,140 patients with type 2 diabetes

6. Irrespective of the level of hemoglobin A1c or blood pressure at entry
Hypotheses:
Among individuals with type 2 diabetes, the risks of major microvascular and macrovascular events will be reduced by:
Intensive glucose control with a sulfonylurea (gliclazide-MR) based regimen targeting a hemoglobin A1c of 6.5% of less
Routine BP lowering with a fixed combination of an ACE inhibitor (perindopril) and a diuretic (indapamide)
Irrespective of the level of hemoglobin A1c or blood pressure at entry

7. Relative risk reduction
All-cause mortality 25
Standard
Intensive
Relative risk reduction
7%: 95% CI -6 to 17%
p=0.28 20 15
Cumulative incidence (%) 10 5 6 12 18 24 30 36 42 48 54 60 66
Follow-up (months)

8. Major macrovascular events25
Standard
Intensive
Relative risk reduction
6%: 95% CI: -6 to 16%
p=0.32 20 15
Cumulative incidence (%) 10 5 6 12 18 24 30 36 42 48 54 60 66
Follow-up (months)

9. Average glucose control (HbA1c) is associated with CVD
Every 1% higher HbA1c above 7%
is associated with a 38% higher
risk of macrovascular events
Intensive
All
Standard
Mean HbA1c during follow-up (%)
Zoungas et al. Diabetologia 2012

10. Hospitalisation for CHF
VADT1
(n=1700)
ACCORD2
(n=10,250)
ADVANCE3
(n=11,140)
HbA1c at end of follow up: standard vs intensive
8.4 vs 6.9
7.5 vs 6.4
7.3 vs 6.5
Primary endpoint
Non-fatal MI
Non-fatal stroke
CVD death
Hospitalisation for CHF
Revascularisation
Hazard ratio for primary outcome (95% CI)
0.87
(0.730 – 1.04)
0.90
(0.78 – 1.04)
0.94
(0.84 – 1.06)
Hazard ratio for mortality (95% CI)
1.065 (0.801 – 1.416)
1.22 (1.01 – 1.46)
0.93 (0.83 – 1.06) *
*p=0.04
1 Duckworth W et al for the VADT Investigators. N Engl J Med 2009; 360: 129–39. 2The ACCORD Study Group N Engl J Med 2008;358: ;
3The ADVANCE Collaborative Group N Engl J Med 2008,358:

11. Mortality (meta-analysis)
Hazard ratio (95% CI)
UKPDS
0.94 (
0.80 ,
1.10 )
ADVANCE
0.93 (
0.83 ,
1.06 )
VADT
1.07 (
0.80 ,
1.40 )
ACCORD
1.22 (
1.01 ,
1.46 )
Overall
0.5 1 2
Risk ratio (95% CI)
Favors intensive glucose control
Favors standard glucose control

12. No mortality benefit and at what cost?
140
+40%*
Intensive control
120
100
Standard control 80
Events per 100 patient years 60 40
+87%* 20
0.7
0.4
Minor hypoglycaemia
Severe hypoglycaemia
*p<0.001

13. Hypoglycaemia and CVD
Hypoglycaemia is an independent risk factor for serious cardiovascular events
Triggers paroxysmal neurohormonal surges
Higher frequency of ischemic ECG changes when glucose levels fall < 4 mM
Increases in the corrected QT interval
Cause for autonomic neuropathy
? Prothrombotic
The risks of recurrent or severe hypoglycemia sometimes supersede the CV benefits of improved glycemic control.

14. Hypoglycaemia and CVD
“ Since hypoglycemia may exacerbate myocardial ischemia and may cause dysrhythmias, it follows that those medications that predispose patients to this adverse event
should be avoided if possible (in patients with or at risk of CVD)”
Joint ADA and EASD position statement 2012
Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

15. Cardiovascular Events
Non-Fatal MI, Stroke or CVD Death
0.12
0.10
Risk reduction 57%
95% CI: 12, 79
Log-rank P = 0.018
0.08
Cumulative Incidence
0.06
Conventional
0.04
0.02
Intensive
0.00
Years from Study Entry
Number at Risk
Intensive:
Conventional:
DCCT/EDIC Study Research Group, NEJM 2005

16. Pharmacological treatment of hyperglycaemia - overweight or obese person

17. Metformin as First Line Therapy
Evidence-informed Consensus
Effective
Favourable effect on weight, low risk of hypoglycaemia, and low cost
Caution with renal insufficiency presents a major implementation challenge in many parts of the world
Possible CVD benefit

18. STOP-NIDDM trial: Lower incidence of cardiovascular events in acarbose treated patients
JL, Josse RG, Gomis R, et al. STOP-NIDDM trial. JAMA 2003; 290: 486–494

19. New over last few years DPP-4 inhibitors GLP-1 analogues
HbA1c for diagnosis of diabetes
Community diabetes prevention programs
Available new therapies
DPP-4 inhibitors
GLP-1 analogues
TZDs less favoured
Multi-factorial interventions
Large scale clinical trials

20. Disappointment of glucose lowering studies
Turnbull et al. Intensive glucose control and macrovascular
outcomes in type 2 diabetes. Diabetologia 52, , 2009

21. Time to Onset of First Primary Major Adverse Cardiovascular Event (MACE)
Controlled Phase 2b/3 Pooled Population 5 4 3
Percentage With First Adverse Event
Control 2
All Saxagliptin 1
Reference
Frederich R et al. Postgrad Med. 2010;122:16-27.
Key Point
The time to onset of the first primary MACE was delayed in saxagliptin patients versus controls. The Kaplan-Meier curves diverged within the first few weeks of treatment.
Additional Details
Primary MACE was defined as myocardial infarction, stroke, or CV-death (defined using a MedDRA (Medical Dictionary for Regulatory Activities, version 11.0) preferred term list selective for these events and supplemented by clinical review of all deaths). BL 24 37 50 63 76 89
102
115
128
Patients at Risk
Control
1251
935
860
774
545
288
144
123
102 57
All Saxagliptin
3356
2615
2419
2209
1638
994
498
436
373
197
Weeks
Frederich R et al. Postgrad Med. 2010;122:16-27.

22. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE)
CAROLINA : An Active Comparator (glimepiride) CARdiOvascular Outcome Study of the DPP-4 Inhibitor LINAgliptin in Patients with Type 2 Diabetes at High Cardiovascular Risk
Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study

23. Interventions within the incretin axis
Analogs
Ingestion of food
GI tract
GLP1
GIP
Promotes insulin secretion
Retards glucagon release
Beta cell proliferation
Slows gastric emptying
Reduces appetite
DPP4 + -
L-cells
GLP-R
Note: slide builds to show actions
Key points
Incretins (GLP-1 and GIP) are intestinal hormones involved in regulating glucose homeostasis – their effects are glucose dependent.
Incretins are released by the intestine throughout the day and levels increase after meals.
When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic β cells by intracellular signalling pathways involving cyclic AMP.
Enhanced tissue glucose uptake occurs with higher insulin levels
GLP-1 also lowers glucagon secretion from pancreatic α-cells
Decreased glucagon levels, along with higher insulin levels, lead to less hepatic glucose production and a decrease in fasting and postprandial blood glucose levels.
Reference
Drucker DJ. Cell Metab. 2006;3:
Ludwig DS. JAMA. 2002;287:
DPP4
DPP4 +
Gliptins 23